Anti selective glycolate aldol reactions of (: S)-4-isopropyl-1-[(R)-1-phenylethyl]imidazolidin-2-one: application towards the asymmetric synthesis of 8-4′-oxyneolignans

Article abstract of DOI:10.1039/c6ra22026f

The anti selective glycolate aldol reactions of (S)-4-isopropyl-1-[(R)-1-phenylethyl]imidazolidin-2-one auxiliary have been standardized with high yields and excellent diastereoselectivities on various substituted aryl, allyl and alkyl aldehydes. The optimized reaction conditions were employed for the stereoselective synthesis of oxyneolignans.

Full text of DOI:10.1039/c6ra22026f

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Journal Name
RSCPublishing
ARTICLE
Anti selective glycolate aldol reactions of (S)-4-
isopropyl-1-[(R)-1-phenylethyl]imidazolidin-2-one:
application towards the asymmetric synthesis of 8-4'-
oxyneolignans
Cite this: DOI: 10.1039/x0xx00000x
Received 00th January 2012,
Accepted 00th January 2012
Mukesh Gangar, Avinash Ittuveetil, Sandeep Goyal, Anang Pal, Harikrishnan M.,
Vipin A. Nair*
DOI: 10.1039/x0xx00000x
www.rsc.org/
The anti selective glycolate aldol reactions of (S)-4-isopropyl-1-[(R)-1-phenylethyl]imidazolidin-2-one
auxiliary have been standardized with high yields and excellent diastereoselectivities on various
substituted aryl, allyl and alkyl aldehydes. The optimized reaction condition was employed for the
stereoselective synthesis of oxyneolignans.
afford the anti 1,2ꢀdiols, with inadequate scope for a broad
substrate generalization.2d,2g,2h,2i Among them, the tin enolates
Introduction
The glycolate aldol reaction is a convenient method to access
1,2ꢀdiols, and serves as an attractive alternative to
dihydroxylation of double bonds.1 Through energetically
differing transition states, stereoselective aldol reactions offer
the advantage of yielding one of the isomers preferentially.
Chiral auxiliary mediated glycolate aldol reactions provide a
robust method for the stereoselective synthesis of 1,2ꢀdiols,2
while only a few chiral catalysts and ligands are yet known to
promote the reaction.3 Glycolate esters of oxazolidinone and
oxazolidinethione based chiral auxiliaries have been employed
to demonstrate syn 1,2ꢀdiol formation by the intermediacy of
boron and titanium enolates, respectively.2c,2k On the contrary,
the anti selective 1,2ꢀdiol formation is innately more
challenging, and is assumed to be due to the difficulty in
of oxazolidinone and thiazolidinone had revealed a biasness for
the formation of anti glycolate aldol adducts, though the
yield/selectivity was insufficient.2f The stereoselective
glycolate aldol reactions of boron enolate of a chiral oxapyrone
exhibited anti diastereoselectivity.2g The reaction employed
stoichiometric excess of the reagents for enolization, affording
attaining an
Eꢀenolate geometry in the transition state with
many of the chiral auxiliaries. The available information from
literature indicate that only a few chiral auxiliaries are known to
Figure 1. A few auxiliaries used for glycolate aldol reaction
Department of Medicinal Chemistry, National Institute of Pharmaceutical
Education and Research, Sector 67, Mohali, Punjab 160062, India
* Corresponding Author; Eꢀmail: vn74nr@yahoo.com, Fax: 91-172-2214692
only moderate yields and stereoselectivities with aromatic and
α,
β
ꢀunsaturated aldehydes. With a substrate limitation of the
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DOI: 10.1039/C6RA22026F
presence of an alkoxy group on aldehydes, and a condition of 1H NMR spectrum of the crude product
.
The scope of the
precomplexation with TiCl4, high anti diasteroselectivity reaction was examined by extending the reaction condition to
was illustrated in glycolate aldol reactions involving titanium different aldehydes and excellent anti diastereoselectivity was
enolates of
N
ꢀglycolylselones.2i Another improvement in this obtained in all the cases, including aromatic, heteroaromatic
direction was demonstrated with the oxazolidinethione and
glycolate. Despite the reasonably good anti diasteroselectivity
obtained in the reactions with aliphatic aldehydes, titanium
α,βꢀunsaturated aldehydes (Table 1).
Table 1. Glycolate aldol reactions of (S)ꢀ4ꢀisopropylꢀ1ꢀ(R)ꢀ1ꢀ
enolate of the Nꢀglycolyloxazolidinethione also necessitated the
phenylethyl]imidazolidinꢀ2ꢀone
precomplexation of aldehydes with excess of TiCl4.2h The
boron enolate generated from the glycolate ester of the benzyl
Entry
Substrate
Product
Yield
(%)
85
86
88
79
78
75
71
80
70
76
82
85
82
78
dr (anti1:
Σ anti2, syn)
98:2
protected thiol variant of
auxiliary illustrated anti diasteroselectivity.2d However the
facial selectivity was unsatisfactory, and a switch over to tert
a norephedrineꢀderived chiral
1
2
3
Benzaldehyde
4ꢀFluorobenzaldehyde
4ꢀChlorobenzaldehyde
4ꢀBromobenzaldehyde
4ꢀMethylbenzaldehyde
2ꢀMethylbenzaldehyde
Furanꢀ2ꢀcarboxaldehyde
2ꢀMethylbutꢀ2ꢀenal
Isovaleraldehyde
3a
3b
3c
3d
3e
3f
3g
3h
3i
98:2
98:2
98:2
96:4
93:7
98:2
95:5
95:5
ꢀ
4
butyldiphenylsilyl protecting group was essential. Imposed by
the condition employed for the cleavage of the auxiliary from
the aldol adduct, in some cases the limitations also included the
difficulty in recovering the chiral auxiliary for further use. The
predicaments demand an alternative for the synthesis of anti
1,2ꢀdiols. Recently we observed a reversal in selectivity from
syn to anti aldol adducts in the acetate aldol reactions of an Lꢀ
5
6
7
8
9
10
11
12
13
14
Cinnamaldehyde
3j
96:4
97:3
96:4
Propionaldehyde
4ꢀOTBS vanillin
3k
3l
4ꢀOTBS syringaldehyde
Isobutyraldehyde
3m
3n
95:5
96:4
valine derived chiral auxiliary,
(S)ꢀ4ꢀisopropylꢀ1ꢀ(R)ꢀ1ꢀ
phenylethyl]imidazolidinꢀ2ꢀone by changing the enolate metal
counter ion from titanium to lithium.4 Perceptions in this
direction prompted us to explore the glycolate aldol reactions of
the auxiliary by generating the lithium enolate. We reasoned
that the attempt would provide an easy access to the
stereochemically defying anti 1,2ꢀdiol synthesis. Elaboration of
the use of the imidazolidinꢀ2ꢀone chiral auxiliary to variations
of the aldol reaction theme would also exemplify its versatility,
the stereoselectivity arising from the dual stereochemical
controls consisting of the isopropyl group residing on the
heterocycle that induces the facial biasness, and the exocyclic
αꢀmethyl benzyl substituent that augments the stereoselection
by a synchronous electronic effect.
a: diastereomeric ratio was determined from the 1H NMR spectrum of the
reaction mixture
Scheme 2. Determination of absolute configuration
To determine the absolute configuration aldol adduct 3l was
reductively cleaved and subsequently deprotected to give
4 in
75% isolated yield over steps Scheme ). The
3
(
2
diastereoselectivity observed can be explained by the transition
states depicted in Scheme 3. Reaction of the acylated chiral
auxiliary with LiHMDS is expected to generate the (Z) enolate
Scheme
phenylethyl]imidazolidin-2-one
1.
Glycolate
aldol
reaction
of
(S)-4-isopropyl-1-(R)-1-
The
of the chiral auxiliary (
imidazolidinꢀ2ꢀone with NaH in freshly dried THF followed
by the treatment with benzyloxyacetyl chloride to afford the
acylated chiral auxiliary in 82% yield. Evaluation of the aldol
reaction was carried out by generating the lithium enolate of
benzyl protected ꢀglycolylꢀ( )ꢀ4ꢀisopropylꢀ1ꢀ( )ꢀ1ꢀ
phenylethyl]imidazolidinꢀ2ꢀone Scheme ). Among the
Nꢀacylation reaction was carried out by the deprotonation
S
)ꢀ4ꢀisopropylꢀ1ꢀ(( )ꢀ1ꢀphenylethyl)
R
1
2
N
S
R
(
1
different lithium bases employed for enolate generation
LiHMDS afforded the best result. A preliminary reaction with
benzaldehyde afforded high diastereoselectivity of 98:02 in
favor of the anti glycolate aldol adduct as determined from the
2 | J. Name., 2012, 00, 1-3
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Scheme 3. Possible transition state for the lithium mediated glycolate aldol
reaction
Scheme 4. Cleavage of the chiral auxiliary
Encouraged by the high anti diastereoselectivity obtained in the
preferentially. Attack of the enolate from its Re face to the Re glycolate aldol reactions we decided to extend the strategy
towards the synthesis of 8ꢀ4'ꢀoxyneolignans. Lignans, the
products of shikimic acid pathway, encompass compounds
containing two phenyl propanoid (C6ꢀC3) units joined together
at C8 and C8'. Neolignans on the other hand, are composed of
two C6ꢀC3 units which are linked via carbon atoms other than
C8 while the subclass of oxyneolignans have their C6ꢀC3 units
not directly joined but connected via an ether linkage. The
locants of the two positions linked by the ether oxygen are cited
in front of the name with the second number primed.4 The 8ꢀ4'ꢀ
oxyneolignans have become the subject of extensive research
lately due to their vast pharmocological profile, which includes
face of the aldehyde is energetically favored over the Si face of
the aldehyde, through transition state (TSꢀA) to afford the
glycolate anti aldol isomer as the major product.
Cleavage of the auxiliary from the aldol adduct under different
conditions afforded the functionally modified 1,2ꢀdiols. For
instance, sodium borohydride mediated reduction in methanol
gave the synthetically useful propaneꢀ1,2,3ꢀtriol unit
7 wherein
one of the secondary hydroxyl groups is selectively protected
by a benzyl group. Such a selective protection on 1,2,3ꢀtriols is
normally difficult to achieve. Similarly, reactions of the aldol
adducts with amines and alcohols yielded the amide and ester
derivatives of 1,2ꢀdiols, respectively. The mild procedure of
subjecting an aldol intermediate to hydrogen peroxide in
presence of a base revealed the corresponding carboxylic acid
antimalarial,
antiparasitic,
antifungal,
antioxidant,
antileishmanial, antiꢀ schistosomial and anticancer properties 5
.
OH
OH
OH
OH
OMe
MeO
MeO
MeO
MeO
(
Scheme 4). In all these cases the chiral auxiliary was
O
O
O
O
OH
OH
OH
OH
OH
OH
OH
succesfully recovered in good yields (85ꢀ88%) by column
chromatographic methods, for recycling. The anti 1,2ꢀdiol
selectivity and absolute configuration were ascertained by
MeO
HO
OH
HO
MeO
MeO
OMe
OMe
OMe
OMe
Figure 3. Structurally diverse oxyneolignans
comparing the optical rotation of compound
literature and also by single crystal Xꢀray diffraction analysis of
compound 3a Figure 2).
4 with that of the
Wide range of substituents have been observed in these
molecules which contribute to the diverse chemical features and
(
biological activities. 8ꢀ4'ꢀOxyneolignans having 3ꢀhydroxyꢀ(E)ꢀ
propꢀ1ꢀenyl side chain in the erythro and threo forms and 3ꢀ
hydroxy propyl side chains are found in several natural sources.
Despite the difficulties in the isolation of this
pharmacologically active ingredient from the natural sources,
OH
O
OEt
O
OEt
O
OEt
O
R
R
O
O
Xc
OH
OH
OH
O
R
R
O
OH
Xc
R'
R'
Scheme 5. Retrosynthetic scheme for 8-4'-oxyneolignans
Figure 2. Ortep diagram of compound 3a
O
OEt
O
H
O
H
(E)
1. triethyl phosphono
TBSCl, imadazole
acetate, DBU, rt, neat, 4h
2. DBU CH3CN:H2O
OMe
O
OH
DCM, 0 0
OMe 1h
C
OH
(R)
(R)
HO
(S)
MeO
MeO
(R)
H2O2,
HO
rt, 3h
OBn
MeO
OMe
OTBS
OH
LiOH.H2O,
THF:H2O, rt
OBn
OH
5
85%
NaBH4,
MeOH, rt
9
92%
7
10, Ethyl sinapate
O
OEt
88%
O
OH
O
OH
90% over 2 steps
O
(E)
(E)
(R)
N
(S)
(R)
EtOH, cat.H2SO4
4h
N
Ph(R)
OBn
NH2
EtOH, K2CO3,
rt
OMe
3a
OMe
O
OH
OH
THF, rt
O
OH
OH
(R)
(R)
11, Ethyl ferulate
BnHN
(R)
EtO
(R)
94%
OBn
OBn
6
8
78%
90%
Scheme 6. Synthesis of ethyl sinapate and ethyl ferulate
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butyldimethylsilyl chloride and thereafter subjected to
o
no stereoselective synthetic procedures have been reported till
enolization using LiHMDS in THF at ꢀ78 C. The reaction of
date. Taking further strides, we explored
a
suitable
the corresponding lithium enolate with the different aldehydes
afforded the anti aldol derivatives 15(a-c). The chiral auxiliary
was removed by a reductive cleavage employing NaBH4 in
THFꢀH2O medium at room temperature. Reaction with
tetrabutylammonium fluoride in THF at room temperature
retrosynthetic pathway for the asymmetric synthesis of the
template. The synthesis of the guiacol ether commenced with a
silyl protection of 4ꢀhydroxyꢀ3,5ꢀdimethoxybenzaldehyde
(syringaldehyde) using tertꢀbutyldimethylsilyl chloride and
imidazole in DCM at 0 °C (Scheme 6). The protected
afforded the corresponding oxyneolignans 16(a-c) (Scheme 7)
.
benzaldehyde
9 was subjected to HornerꢀWadsworthꢀEmmons
The allylic side chain of oxyneolignan 16a was reduced by
catalytic hydrogenation using Pd/C in ethyl acetate at room
temperature to give the corresponding oxyneolignan 17. The
anti glycolate aldol stereochemistry was confirmed by
comparing the coupling constant (reported J7,8 = 3.5 Hz,
observed J7,8 = 3.5 Hz). The absolute configuration was
reaction employing triethylphosphonoacetate and DBU at room
temperature under neat conditions to obtain the corresponding
conjugated ester. The silyl protection was then removed using
DBU in acetonitrileꢀwater mixture at room temperature to give
ethyl sinapate 10. Similarly the monomethoxy analogue ethyl
ferulate 11 was synthesized from commercially available
ferulic acid by Fischer esterification.
18
established by correlation of the optical rotation [reported [α]D
7.7 (c 1.9, MeOH), observed [α]D20 9.2 (c 1.9, MeOH)].
The esters 10
& 11 were converted to the corresponding
alcohols using a combination of lithium aluminium hydride and
benzyl chloride in THF at 0 C to obtain coniferyl alcohol 13a
Conclusions
o
The anti glycolate aldol reaction of benzyloxy acetyl
and sinapyl alcohol 13b, respectively. The bromoacetyl
derivatives of
(S)ꢀ4ꢀisopropylꢀ1ꢀ(R)ꢀ1ꢀphenylethyl]imidazꢀ
olidinꢀ2ꢀone has been succesfully standardised with high yields
and diastereoselectivity. Further its application in the total
synthesis of naturally occuring 8ꢀ4'ꢀoxyneolignans was
demonstrated.
Acknowledgements
Financial assistance in the form of a Senior Research
Fellowship from CSIR to M.G. is gratefully acknowledged. We
are thankful to Dr. Angshuman Roy Choudhury, IISER Mohali
for Xꢀray crystallographic data.
Experimental
All the reagents required for this study were purchased from
commercial sources and used as such without further
1
purification. Solvents were distilled and dried before use. H
and 13C NMR spectra were recorded at 400 and 100 MHz,
respectively, on a Bruker Avance DPX 400 (400 MHz)
spectrometer in CDCl3/CD3OD using TMS as an internal
1
standard. The chemical shifts (
δ
) for H and 13C spectra are
given in ppm relative to residual signals of the solvent.
Coupling constants are given in Hz. The following
abbreviations are used to indicate multiplicity: s, singlet; d,
doublet; t, triplet; td, triple doublet; dt, double triplet; q, quartet;
m, multiplet; brs, broad signal. HRMS were recorded on a
Bruker Maxix TOF mass spectrometer. Melting points are
uncorrected. IR spectra were recorded on a Perkin Elmer FTIR
spectrophotometer.
Scheme 7. Total synthesis of oxyneolignans
derivative of
idin2ꢀone was prepared by deprotonation of the chiral auxiliary
with NaH in dry THF followed by treatment with
bromoacetyl bromide. Reaction of 13a 13b with the
(S)ꢀ4ꢀisopropylꢀ1ꢀ[(R)ꢀ1ꢀphenylethyl]imidazolꢀ
1
Crystallographic data for the compound 3a has been deposited
with the Cambridge Crystallographic Data Centre, CCDC No.
1452671. Copies of the data can be obtained free of charge on
application to CCDC, 12 Union Road, Cambridge CB2 1EZ,
&
bromoacetylated chiral auxiliary 12 and potassium carbonate in
acetone along with the catalytic amount of KI at room
temperature afforded the aryloxy acetyl derivatives 14a
&
14b
.
Subsequently the allylic alcohol was protected using tert
ꢀ
4 | J. Name., 2012, 00, 1-3
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UK,
(fax:
+44ꢀ(0)1223ꢀ336033
or
eꢀmail: dried over anhydrous sodium sulfate. The crude reaction
mixture was purified by column chromatography using silica
gel (60ꢀ120 mesh) by eluting with petroleum ether/EtOAc
deposit@ccdc.cam.ac.uk).
Synthesis of (
1-phenylethyl)imidazolidin-2-one
To a stirring solution of ( )ꢀ4ꢀisopropylꢀ1ꢀ((
imidazolidinꢀ2ꢀone (2.0 g, 8.6 mmol, 1.0 equiv.) in anhydrous l)-4-isopropyl-1-((
THF, sodium hydride (60% suspension in paraffin oil, 0.41 g, Yield = 85%; Crystalline solid, m.p. = 85ꢀ86 °C. [α]D20 = +99.7
S
)-3-(2-(benzyloxy)acetyl)-4-isopropyl-1-((
R)- (60:40) to afford the desired product (0.77 g, 85%).
(
2a):
S
R
)ꢀ1ꢀphenylethyl)
(
S
)-3-((2
R,3
R)-2-(benzyloxy)-3-hydroxy-3-phenylpropanoy
R
)-1-phenylethyl)imidazolidin-2-one 3a)
(
°
1
10.3 mmol, 1.2 equiv.) was slowly added at 0 C under inert (c 1, CHCl3); H NMR (400 MHz, CDCl3)
atmosphere. After 1h, benzyloxyacetyl chloride (1.43 mL, 9.0 Hz, 3H), 0.87 (d, = 7.0 Hz, 3H), 1.59 (d,
mmol, 1.05 equiv.) was added dropwise. Reaction mixture was 2.33ꢀ2.41 (m, 1H), 2.88 (t, = 9.4 Hz, 1H), 3.08 (dd,
stirred for another hour. Completion of the reaction was 9.7 Hz, 1H), 3.98ꢀ4.02 (m, 1H), 4.08 (d, = 9.8 Hz, 1H), 4.34
monitored by TLC. The reaction mixture was then quenched by (d, = 11.8 Hz, 1H), 4.42 (d, = 11.8 Hz, 1H), 4.85 (dd,
dropwise addition of aq. NH4Cl at 0 °C, washed with water and 8.3, 9.7 Hz, 1H), 5.35 (q, = 7.2 Hz, 1H), 5.52 (d, = 8.2 Hz,
extracted with ethyl acetate. The organic layer was dried over 1H), 7.06ꢀ7.17 (m, 5H), 7.30ꢀ7.47 (m, 8H), 7.52ꢀ7.55 (m, 2H);
anhydrous sodium sulfate. It was evaporated under vacuum to 13C NMR (100 MHz, CDCl3)
14.47, 16.06, 17.99, 28.78,
δ
J
0.75 (d,
= 7.2 Hz, 3H),
= 2.3,
J = 6.9
J
J
J
J
J
J
J =
J
J
δ
give a solid compound which was purified by column 37.66, 50.60, 55.79, 72.98, 75.21, 79.39, 126.97, 127.26,
chromatography on silica gel (60ꢀ120 mesh) using ethyl 127.64, 127.73, 128.06, 128.18, 128.26, 128.47, 128.81,
acetateꢀhexane (01:09) mixture as eluent.
137.29, 138.74, 141.95, 155.12, 171.75; ESIꢀHRMS (m/z):
20
Yield = 82%, White solid, m.p. = 69 °C, [α]D = +89.1 (c 1, [M+Na]+ calculated for C30H34N2NaO4, 509.2416, found,
1
CHCl3); H NMR (400 MHz, CDCl3)
δ
0.81 (d,
= 7.1 Hz, 1H), 2.42–
= 3.0, 9.6 Hz, isopropyl-1-((
= 11.7 Hz, 1H), 4.76 (d, Yield = 88%; gummy. [α]D = +74.3 (c 1, CHCl3); H NMR
= 7.1 Hz, 1H), 7.28–7.36 (m, 8H), 7.40– (400 MHz, CDCl3) 0.77 (d, = 6.9 Hz, 3H), 0.90 (d, = 7.0
7.42 (m, 2H); 13C NMR (100 MHz, CDCl3)
14.39, 16.12, Hz, 3H), 1.61 (d, = 7.2 Hz, 3H), 2.36 – 2.44 (m, 1H), 3.01 (t,
18.01, 28.48, 37.81, 50.32, 54.87, 70.03, 73.41, 127.15, 127.78, = 9.4 Hz, 1H), 3.14 (dd, = 2.4, 9.8 Hz, 1H), 3.25 (s, 3H),
128.00, 128.07, 128.41, 128.77, 137.70, 138.83, 154.40, 4.04 (d, = 8.4 Hz, 1H), 4.28ꢀ4.32 (m, 1H), 4.83 (t, = 8.4 Hz,
170.47; ESIꢀHRMS (m/z): [M+Na]+ calculated for 1H), 5.40 (q,
= 7.1 Hz, 1H), 5.43 (d, = 7.7 Hz, 1H), 7.30ꢀ
C23H28N2NaO3, 403.1998, found, 403.1998. 7.42 (m, 8H), 7.53 (d,
= 7.2 Hz, 2H); 13C NMR (100 MHz,
CDCl3) 14.37, 16.10, 18.03, 28.68, 37.64, 55.71, 58.31,
J
= 6.8 Hz, 534.2416.
3H), 0.88 (d,
2.50 (m, 1H), 2.96 (t,
1H), 4.18–4.22 (m, 1H), 4.66 (q,
1.9 Hz, 1H), 5.28 (q,
J
= 6.8 Hz, 3H), 1.55 (d,
J
(
S
)-3-((2
R,3
R)-3-hydroxy-2-methoxy-3-phenylpropanoyl)-4-
J
= 9.6 Hz, 1H), 3.10 (dd,
J
R
)-1-phenylethyl)imidazolidin-2-one (3a’)
20
1
J
J =
J
δ
J
J
δ
J
J
J
J
J
J
J
J
δ
(
S
)-4-isopropyl-3-(2-methoxyacetyl)-1-((
R
)-1-phenylethyl)
74.99, 77.25, 81.78, 126.86, 127.20, 127.80, 128.15, 128.32,
128.85, 138.60, 141.71, 155.17, 171.48; ESIꢀHRMS (m/z):
imidazolidin-2-one (2a’)
White solid; Yield: 78%; m.p.: 88 °C; [α]D +110.1 (c 1.0, [M+Na]+ calculated for C24H30N2NaO4, 433.2103, found,
20
1
CHCl3); H NMR (400 MHz, CDCl3)
δ
0.82 (d,
= 7.2 Hz, 3H), 2.41ꢀ
= 9.5 Hz, 1H), 3.12 (dd, = 3.0, 9.6 Hz,
1H), 3.49 (s, 3H), 4.21 (dt, = 3.3, 9.4 Hz, 1H), 4.65 (d,
17.5 Hz, 1H), 4.71 (d, = 17.5 Hz, 1H), 5.30 (q, = 7.1 Hz, 2-one
1H), 7.29ꢀ 7.39 (m, 5H); 13C NMR (100 MHz, CDCl3)
16.13, 17.99, 28.52, 37.90, 50.36, 54.82, 59.36, 72.43, 127.14, (400 MHz, CDCl3)
128.78, 128.01, 138.87, 154.44, 170.32; IR (cmꢀ1): ῡ = 3444, Hz, 3H), 1.56 (d,
2963, 1719, 1495, 1428, 1304, 1262, 1202, 1130, 933, 891, = 9.4 Hz, 1H), 3.06 (dd,
J = 6.9 Hz, 433.2101.
3H), 0.89 (d,
2.49 (m, 1H), 2.98 (t,
J = 7.0 Hz, 3H), 1.57 (d, J
J
J
(
S
)-3-((2
propanoyl)-4-isopropyl-1-((
3b
R,3R)-2-(benzyloxy)-3-(4-fluorophenyl)-3-hydroxy
J
J
=
R
)-1-phenylethyl)imidazolidin-
J
J
(
)
20
1
δ
14.44, Yield = 86%; gummy. [α]D = +94.3 (c 1, CHCl3); H NMR
δ
0.73 (d,
= 7.2 Hz, 3H), 2.29ꢀ2.37 (m, 1H), 2.86 (t,
= 11.9 Hz, 1H), 3.95ꢀ3.99 (m, 1H),
= 9.1 Hz, 1H), 4.32 (d, = 11.8 Hz, 1H), 4.38 (d,
11.8 Hz, 1H), 4.81 (t, = 8.6 Hz, 1H), 5.31 (q, = 7.1 Hz, 1H),
5.43 (d, = 8.1 Hz, 1H), 7.01ꢀ7.10 (m, 6H), 7.11ꢀ7.16 (m, 1H),
7.31ꢀ7.48 (m, 7H); 13C NMR (100 MHz, CDCl3)
14.47,
J = 6.9 Hz, 3H), 0.85 (d, J = 7.0
J
J
J
764, 702, 647, 547; HRMS (ESIꢀTOF) calcd for C17H24N2O3Na 4.15 (d,
[M+Na]+: 327.1685; found: 327.1671.
J
J
J =
J
J
J
General procedure for the aldol reaction.
δ
To the solution of (
[( )ꢀ1phenylethyl]imidazolidinꢀ2ꢀone (3) (0.6 g, 2.2 mmol, 1.0 114.90, 115.11, 127.25, 127.74, 128.10, 128.23, 128.50,
equiv.) in freshly dried THF (5 mL) under N2 environment and 128.64, 128.72, 128.84, 137.12, 137.87, 137.90, 138.69,
cooled to 78 °C was added LiHMDS solution (2.4 mL, 2.4 155.14, 161.18, 163.62, 171.56
ESIꢀHRMS (m/z): [M+Na]+
S)ꢀ3ꢀ[2ꢀ(benzyloxy)acetyl]ꢀ4ꢀisopropylꢀ1ꢀ 16.08, 17.97, 28.82, 37.71, 50.67, 55.83, 72.98, 74.55, 79.36,
R
–
;
mmol, 1.1 equiv.; 1M in THF) at ‒78°C, and stirred for 1 h. calculated for C30H33FN2NaO4, 527.2322, found, 527.2326.
Benzaldehyde (0.25 mL, 2.4 mmol, 1.1 equiv.) was added to
the reaction mixture and further stirred for 30 minutes. The
(S)-3-((2R,3R)-2-(benzyloxy)-3-(4-chlorophenyl)-3-hydroxy
reaction was quenched by saturated aq NH4Cl solution, and propanoyl)-4-isopropyl-1-((
R
)-1-phenylethyl)imidazolidin-
extracted with EtOAc which was further washed with brine and 2-one (3c)
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 5

RSC Advances
Page 6 of 13
ARTICLE
VJieowuArrtnicalelONnlainme e
DOI: 10.1039/C6RA22026F
20
Yield 88%; gummy. [α]D +88.9 (c 1, CHCl3);1H NMR (400
J
= 4.4 Hz, 4H), 7.14ꢀ7.29 (m, 4H), 7.33ꢀ7.40 (m, 3H), 7.42ꢀ
MHz, CDCl3)
δ
0.75 (d,
= 7.2 Hz, 3H), 2.31ꢀ2.39 (m, 1H), 2.88 (t,
= 2.2, 9.7 Hz, 1H), 3.97ꢀ4.01 (m, 1H), 126.24, 127.28, 127.46, 127.61, 128.06, 128.18, 128.33,
= 9.7 Hz, 1H), 4.35 (d, = 11.8 Hz, 1H), 4.42 (d, 128.83, 130.16, 136.64, 137.46, 138.79, 140.31, 154.99,
11.8 Hz, 1H), 4.82 (t, = 9.0 Hz, 1H), 5.34 (q,
= 7.1 Hz, 1H), 172.04; ESIꢀHRMS (m/z): [M+Na]+ calculated for
5.44 (d, = 8.2 Hz, 1H), 7.05ꢀ7.19 (m, 5H), 7.33ꢀ7.36 (m, 4H), C31H36N2NaO4, 523.2573, found, 523.2561.
7.37ꢀ7.47 (m, 5H); 13C NMR (100 MHz, CDCl3)
14.44,
16.08, 17.97, 28.83, 37.71, 50.69, 55.84, 73.02, 74.54, 79.20,
127.25, 127.77, 128.11, 128.25, 128.34, 128.40, 128.55, noyl)-4-isopropyl-1-((
128.85, 133.43, 137.02, 138.65, 140.57, 155.16, 171.47; ESIꢀ 3g
HRMS (m/z): [M+Na]+ calculated for C30H33ClN2NaO4, Yield = 71%; gummy. [α]D = +117.7 (c 1, CHCl3); H NMR
543.2027, found, 543.2029. (400 MHz, CDCl3) 0.80 (d, = 6.9 Hz, 3H), 0.88 (d, = 7.0
Hz, 3H), 1.59 (d, = 7.2 Hz, 3H), 2.36ꢀ2.44 (m, 1H), 2.90 (t,
= 9.4 Hz, 1H), 3.09 (dd, = 2.4, 9.7 Hz, 1H), 3.90 (d, = 10.3
Hz, 1H), 4.01ꢀ 4.05 (m, 1H), 4.48 (s, 2H), 4.91 (t, = 9.2 Hz,
1H), 5.38 (q, = 7.1 Hz, 1H), 5.69 (d, = 8.2 Hz, 1H), 6.38
= 1.8, 3.2 Hz, 1H), 6.42 (d, = 3.1 Hz, 1H), 7.12ꢀ7.23
= 7.0 (m, 5H), 7.35ꢀ7.39 (m, 3H), 7.42ꢀ7.45 (m, 3H); 13C NMR
= 7.2 Hz, 3H), 2.29ꢀ2.37 (m, 1H), 2.86 (t, 14.43, 16.04, 17.96, 28.70, 37.68, 50.58, 53.76, 68.71, 73.12,
= 9.4 Hz, 1H), 3.06 (dd, = 2.1, 9.7 Hz, 1H), 3.94ꢀ3.98 (m, 77.68, 108.12, 110.34, 127.29, 127.74, 128.15, 128.48, 128.81,
1H), 4.19 (d, = 8.9 Hz, 1H), 4.32 (d, = 11.8 Hz, 1H), 4.39 137.73, 142.18, 154.13, 154.96, 171.13; ESIꢀHRMS (m/z):
(d, = 11.8 Hz, 1H), 4.78 (t, = 7.6 Hz, 1H), 5.31 (q,
= 7.1 [M+Na]+ calculated for C28H32N2NaO5, 499.2209, found,
Hz, 1H), 5.40 (d, = 8.2 Hz, 1H), 7.07 (d, = 4.3 Hz, 4H), 499.2209.
7.12ꢀ7.17 (m, 1H), 7.29ꢀ7.49 (m, 9H); 13C NMR (100 MHz,
CDCl3) 14.44, 16.07, 17.96, 28.84, 37.73, 50.69, 55.84,
73.01, 74.59, 79.15, 121.64, 127.24, 127.77, 128.12, 128.24, enoyl)-4-isopropyl-1-((
128.54, 128.73, 128.84, 131.28, 137.01, 138.65, 141.07, 3h
155.17, 171.41; ESIꢀHRMS (m/z): [M+Na]+ calculated for Yield = 80%; gummy. [α]D = +107.7 (c 1, CHCl3); H NMR
C30H33BrN2NaO4, 587.1521, found, 587.1531. (400 MHz, CDCl3) 0.81 (d, = 6.9 Hz, 3H), 0.88 (d, = 7.0
Hz, 3H), 1.59 (d, = 6.7 Hz, 3H), 1.67 (d, = 6.7 Hz, 3H), 1.72
(s, 3H), 2.34ꢀ2.42 (m, 1H), 2.88 (t, = 9.4 Hz, 1H), 3.08 (dd,
= 2.3, 9.6 Hz, 1H), 3.58 (d, = 9.0 Hz, 1H), 3.99ꢀ4.03 (m, 1H),
4.23 (t, = 7.6 Hz, 1H), 4.53 (s, 2H), 5.35 (q, = 7.2 Hz, 1H),
Yield = 78%; gummy. [α]D = +86.1 (c 1, CHCl3); H NMR 5.43 (d, = 8.0 Hz, 1H), 5.63 (q, = 6.7 Hz, 1H), 7.13ꢀ7.20 (m,
(400 MHz, CDCl3) 0.76 (d, = 6.9 Hz, 3H), 0.88 (d, = 7.0 3H), 7.26ꢀ7.28 (m, 2H), 7.35ꢀ7.39 (m, 3H), 7.42ꢀ7.46 (m, 2H);
Hz, 3H), 1.59 (d,
= 7.2 Hz, 3H), 2.34ꢀ2.41 (m, 4H; Me, s, 3H 13C NMR 11.41, 13.32, 14.47, 16.07, 17.97, 28.76, 37.56,
& m, 1H merged), 2.87 (t, = 9.4 Hz, 1H), 3.08 (dd, = 2.2, 50.55, 55.66, 72.88, 76.80, 78.45, 123.48, 127.28, 127.71,
9.6 Hz, 1H), 3.97ꢀ4.02 (m, 2H), 4.35 (d, = 11.8 Hz, 1H), 4.45 128.12, 128.16, 128.50, 128.80, 135.01, 137.55, 138.81,
(d, = 11.8 Hz, 1H), 4.83 (t, = 9.1 Hz, 1H), 5.36 (q, = 7.1 155.00, 172.12; HRMS (ESIꢀTOF) calculated for
Hz, 1H), 5.54 (d, = 8.2 Hz, 1H), 7.07ꢀ7.18 (m, 5H), 7.21 (d,
C28H32N2O4Na[M+Na]+: 487.2573; found: 487.2573.
= 7.9 Hz, 2H), 7.33ꢀ7.40 (m, 3H), 7.42ꢀ7.46 (m, 4H); 13C NMR
(100 MHz, CDCl3) 14.47, 16.09, 18.01, 21.23, 28.80, 37.62,
50.60, 55.76, 73.01, 75.05, 79.46, 126.90, 127.28, 127.62, 4-isopropyl-1-((
128.04, 128.19, 128.51, 128.82, 128.95, 137.29, 137.39, Yield = 70%; gummy. [α]D = +67.9 (c 0.5, CHCl3); H NMR
138.79, 139.04, 155.09, 171.88; ESIꢀHRMS (m/z): [M+Na]+ (400 MHz, CDCl3)
(400 MHz, CDCl3) 0.73 (d, = 6.9 Hz,
calculated for C31H36N2NaO4, 523.2573, found, 523.2577. 3H), 0.79 (d, = 7.0 Hz, 3H), 0.84 (d, = 6.6 Hz, 3H), 0.88 (d,
= 6.7 Hz, 3H), 1.45 (t, = 6.8 Hz, 2H), 1.49 (d,
)-2-(benzyloxy)-3-hydroxy-3-(o-tolyl)propanoy 3h), 1.82ꢀ1.89 (m, 1H), 2.27ꢀ2.34 (m, 1H), 2.62 (d,
l)-4-isopropyl-1-(( )-1-phenylethyl)imidazolidin-2-one 3f 1H), 2.82 (t, = 9.4 Hz, 1H), 3.01 (dd,
Yield = 75%; gummy. [α]D = +95.1 (c 1, CHCl3); H NMR 3.82ꢀ3.89 (m, 1H), 3.93ꢀ3.97 (m, 1H), 4.46 (s, 2H), 5.11 (d,
(400 MHz, CDCl3) 0.74 (d, = 6.9 Hz, 3H), 0.89 (d, = 7.0 6.6 Hz, 1H), 5.23 (d, = 7.1 Hz, 1H), 7.07ꢀ7.12 (m, 2H), 7.18ꢀ
Hz, 3H), 1.58 (d,
= 7.1 Hz, 3H), 2.38ꢀ2.47 (m, 4H; Me, 3H & 7.36 (m, 8H); 13C NMR (100 MHz, CDCl3) 14.53, 16.12,
m, 1H, merged), 2.88 (t,
Hz, 1H), 4.02ꢀ4.06 (m, 2H) 4.39 (s, 2H), 5.20 (t,
1H), 5.36 (q, = 7.1 Hz, 1H), 5.67 (d,
J
= 6.9 Hz, 3H), 0.87(d,
J
= 7.0 Hz, 7.46 (m, 2H), 7.62 (d,
J
= 7.4 Hz, 1H); 13C 14.50, 16.07, 18.05,
3H), 1.59 (d,
J
J =
19.56, 28.81, 37.54, 50.58, 55.76, 71.23, 72.89, 79.13, 125.85,
9.4 Hz, 1H), 3.09 (dd,
4.23 (d,
J
J
J
J =
J
J
J
δ
(
S
)-3-((2
R,3
S
)-2-(benzyloxy)-3-(furan-2-yl)-3-hydroxypropa
)-1-phenylethyl)imidazolidin-2-one
R
(
)
20
1
δ
J
J
J
J
(
S
)-3-((2
propanoyl)-4-isopropyl-1-((
2-one 3d
R
,3
R
)-2-(benzyloxy)-3-(4-bromophenyl)-3-hydroxy
J
J
R
)-1-phenylethyl)imidazolidin-
J
(
)
J
J
20
1
Yield = 79%; gummy. [α]D = +73.2 (c 1, CHCl3); H NMR (dd,
J
J
(400 MHz, CDCl3)
Hz, 3H), 1.57 (d,
δ 0.72 (d, J = 6.8 Hz, 3H), 0.85 (d, J
J
J
J
J
J
J
J
J
J
J
δ
(
S
)-3-((2R,3
R
,
E)-2-(benzyloxy)-3-hydroxy-4-methylhex-4-
R)-1-phenylethyl)imidazolidin-2-one
(
)
20
1
δ
J
J
J
J
(
S
)-3-((2
oyl)-4-isopropyl-1-((
3e
R
,3
R
)-2-(benzyloxy)-3-hydroxy-3-(p-tolyl)propan
J
J
R)-1-phenylethyl)imidazolidin-2-one
J
(
)
J
J
J
20
1
J
δ
J
J
J
J
J
J
J
J
J
J
J
δ
(
S
)-3-((2
R,3
R)-2-(benzyloxy)-3-hydroxy-5-methylhexanoyl)-
R
)-1-phenylethyl)imidazolidin-2-one 3i
( )
20
1
δ
J
J
J
J
J
J
= 7.2 Hz,
(
S
)-3-((2
R,3
R
J = 10.1 Hz,
R
(
)
J
J = 2.3, 9.6 Hz, 1H),
20
1
J
=
δ
J
J
J
J
J
= 9.4 Hz, 1H), 3.08 (dd,
J
J
= 2.2, 9.7 17.98, 21.53, 23.98, 24.30, 28.74, 37.62, 43.47, 50.62, 55.51,
= 8.8 Hz, 71.31, 72.98, 80.76, 127.25, 127.76, 128.07, 128.18, 128.60,
J
J = 8.2 Hz, 1H), 7.10 (d,
6 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

Page 7 of 13
Journal Name
RSC Advances
View Article Online
ARTICLE
DOI: 10.1039/C6RA22026F
20
1
128.81, 137.51, 138.85; HRMS (ESIꢀTOF) calculated for Yield = 85%; gummy. [α]D = +103.2 (c 1, CHCl3); H NMR
C32H36N2O4Na[M+Na]+: 535.2573; found: 535.2576.
(400 MHz, CDCl3)
δ
0.18 (d,
J
= 4.3 Hz, 6H), 0.75(d,
J
= 6.9
Hz, 3H), 0.87 (d,
J
= 7.0, 3H), 1.06 (s, 9H), 1.57 (d,
J
= 7.2,
(
S
)-3-((2
enoyl)-4-isopropyl-1-((
3j
Yield = 76%; gummy. [α]D = +136.3 (c 1, CHCl3); H NMR 7.1, 1H), 5.54 (d, J = 8.0, 1H), 6.76 (s, 2H), 7.08ꢀ7.17 (m, 5H),
(400 MHz, CDCl3) 0.75 (d, = 6.9 Hz, 3H), 0.86 (d, ꢀ4.60, ꢀ4.55,
= 7.1 7.32ꢀ7.44 (m, 5H); 13C NMR (100 MHz, CDCl3)
Hz, 3H), 1.58 (d, = 7.2 Hz, 3H), 2.31ꢀ2.40 (m, 1H), 2.91 (t, 14.47, 16.08, 17.99, 18.78, 25.90, 28.80, 37.59, 50.57, 55.70,
= 9.4 Hz, 1H), 3.09 (dd, = 2.4, 9.6 Hz, 1H), 3.48 (d, = 9.4 55.75, 73.01, 75.33, 79.29, 104.00, 127.23, 127.66, 128.05,
Hz, 1H), 4.02ꢀ4.06 (m, 1H), 4.60(s, 2H), 5.34 (q, J = 7.7 Hz, 128.17, 128.43, 128.82, 133.70, 134.41, 138.78, 151.34,
1H), 5.41 (d, = 6.8 Hz, 1H), 6.48 (dd, = 5.6, 16.0 Hz, 1H), 154.94, 171.88; HRMS (ESIꢀTOF) calculated for
6.76 (d,
= 15.4 Hz, 1H), 7.08ꢀ7.28 (m, 4H), 7.31ꢀ7.46 (m, C38H52N2O7SiNa [M+Na]+: 699.3441; found: 699.3448.
11H); 13C NMR (100 MHz, CDCl3)
14.45, 16.11, 17.98,
R
,3
R
,
E
)-2-(benzyloxy)-3-hydroxy-5-phenylpent-4-
3H), 2.33ꢀ2.41 (m, 1H), 2.88 (t,
2.2, 9.7 Hz, 1H), 3.81 (s, 6H), 4.01ꢀ4.05 (m, 1H), 4.13(d,
9.1 Hz, 1H), 4.39(s, 2H), 4.82 (t, J = 8.6 Hz, 1H), 5.34 (q, J =
J
= 9.4 Hz, 1H), 3.07 (dd,
J
J
=
=
R)-1-phenylethyl)imidazolidin-2-one
(
)
20
1
δ
J
J
δ
J
J
J
J
J
J
J
δ
28.76, 37.67, 50.67, 55.64, 73.08, 73.35, 79.39, 126.68, 127.26, (S)-3-((2R,3R)-2-(benzyloxy)-3-hydroxy-4-methylpentanoyl
127.52, 127.86, 128.19, 128.24, 128.45, 128.66, 128.83, )-4-isopropyl-1-((R)-1-phenylethyl)imidazolidin-2-one (3n)
20
1
128.91, 131.27, 136.89, 137.35, 138.80, 154.78, 171.04; HRMS Yield = 78%; gummy. [α]D = +86.3 (c 1, CHCl3); H NMR
(ESIꢀTOF) calculated for C26H34N2O4Na[M+Na]+: 461.2416; (400 MHz, CDCl3)
0.81 (d, = 6.9 Hz, 3H), 0.86 (d, = 7.0
found: 461.2419. Hz, 3H), 0.93 (d, = 6.9 Hz, 3H), 1.03 (d, = 7.0 Hz, 3H), 1.56
= 7.2 Hz, 3H), 2.10ꢀ2.18 (m, 1H), 2.38ꢀ2.49 (m, 1H), 2.88
δ
J
J
J
J
(d,
(t,
J
(
S
)-3-((2
isopropyl-1-((
Yield = 82%; gummy. [α]D = +71.3 (c 1, CHCl3); H NMR = 11.6 Hz, 13.6, 2H), 5.23 (d, J = 9.0 Hz, 1H), 5.32 (q,
(400 MHz, CDCl3) 0.83 (d, = 6.9 Hz, 3H), 0.88 (d,
= 7.0 Hz, 1H), 7.14ꢀ7.20 (m, 2H), 7.28ꢀ7.45 (m, 8H); 13C NMR (100
R,3
R
)-2-(benzyloxy)-3-hydroxypentanoyl)-4-
J
= 9.4 Hz, 1H), 3.07 (dd,
J
= 2.3, 9.7 Hz, 1H), 3.16 (d,
J
=
J
R
)-1-phenylethyl)-imidazolidin-2-one 3k
(
)
11.0 Hz, 1H), 3.62ꢀ3.68 (m, 1H), 3.99ꢀ4.03(m, 1H), 4.50 (dd,
20
1
J
= 7.1
δ
J
J
Hz, 3H), 1.04 (t, J = 7.4 Hz, 3H), 1.54ꢀ1.63 (m, 1H), 1.57 (d,
= 7.2 Hz, 3H), 1.82ꢀ1.92 (m, 1H), 2.38ꢀ2.46 (m, 1H), 2.93 (t,
J
J
MHz, CDCl3)
δ 14.54, 16.01, 17.95, 19.82, 28.77, 29.70, 37.72,
50.54, 55.80, 72.75, 77.16, 127.16, 127.29, 127.86, 128.22,
= 9.4 Hz, 1H), 3.11 (dd,
1H), 4.04ꢀ4.08 (m, 1H), 4.54 (dd,
(d, J = 7.2 Hz, 1H), 5.23 (q, = 7.2 Hz, 1H), 7.18ꢀ7.22 (m, 3H), 475.2557.
7.32ꢀ7.45 (m, 7H); 13C NMR (100 MHz, CDCl3)
9.64, 14.48,
J
= 2.4, 9.7 Hz, 1H), 3.74ꢀ3.81 (m, 128.76, 128.81, 137.33, 138.74, 155.41, 172.78; HRMS (ESIꢀ
J
= 11.5, 15.2 Hz, 2H), 5.23 TOF) calculated for C27H36N2O4Na[M+Na]+: 475.2573; found:
J
δ
16.10, 17.96, 27.35, 28.72, 37.67, 50.61, 55.60, 72.89, 74.43, Synthesis of (1
79.75, 127.25, 127.80, 128.17, 128.22, 128.60, 128.82, 137.48, ne-1,2,3-triol (4)
R
:
,2
S
)-1-(4-hydroxy-3-methoxyphenyl)propa
)ꢀ3ꢀ((2 ,3 )ꢀ2ꢀ(benzyloxy)ꢀ3ꢀ(4ꢀ
138.81, 155.01, 171.95; HRMS (ESIꢀTOF) calculated for To a stirring solution of (
C26H34N2O4Na[M+Na]+: 461.2416; found: 461.2419.
((tertꢀbutyldimethylsilyl)oxy)ꢀ3ꢀmethoxyphenyl)ꢀ3ꢀhydroxyprꢀ
opanoyl)ꢀ4ꢀisopropylꢀ1ꢀ(( )ꢀ1ꢀphenylethyl)imidazolidinꢀ2ꢀone
3l (1.0 g, 1.5 mmol, 1 eq) in MeOH (25) mL was added NaBH4
oxy)-3-methoxyphenyl)-3-hydroxypropanoyl)-4-isopropyl-1- (0.58 g, 15.5 mmol, 10 equiv.) and stirred for 3h. The progress
(( )-1-phenylethyl)imidazolidin-2-one (3l) of the reaction was monitored by TLC. After the completion of
Yield = 85%; gummy. [α]D = +123.5 (c 1, CHCl3); H NMR the reaction, the solvent was evaporated under vacuum. The
S
R R
R
(S)-3-((2R,3R)-2-(benzyloxy)-3-(4-((tert-butyldimethylsilyl)
R
20
1
(400 MHz, CDCl3)
Hz, 3H), 0.88 (d, J = 7.0 Hz, 3H), 1.04 (s, 9H), 1.59 (d,
Hz, 3H), 2.34ꢀ2.42 (m, 1H), 2.89 (t,
= 2.3, 9.7 Hz, 1H), 3.82 (s, 3H), 4.00 (d,
4.05 (m, 1H), 4.38 (d, = 1.9 Hz, 2H), 4.80 (t,
5.35 (q, = 7.2 Hz, 1H), 5.51 (d, J = 8.1 Hz, 1H), 6.88 (d,
8.0 Hz, 1H), 7.00ꢀ7.05 (m, 2H), 7.11ꢀ7.18 (m, 5H), 7.33ꢀ7.45 nitrogen atmosphere and stirred for 30 min at rt until the
(m, 5H); 13C NMR (100 MHz, CDCl3)
ꢀ4.61, ꢀ4.58, 14.49, complete consumption of starting material was observed in
δ
0.19 (d, J = 1.6 Hz, 6H), 0.77 (d,
J
= 6.9 reaction mixture was extracted with EtOAc and the combined
J
= 7.2 organic layers were dried over anhydrous sodium sulfate and
J
= 9.4 Hz, 1H), 3.08 (dd, J concentrated in vacuum. The mixture was taken to the next step
= 9.5 Hz, 1H), 4.02ꢀ without purification.
= 9.1 Hz, 1H), The above product was dissolved in THF (20 mL) and TBAF
(1.55 mL, 1M solution in THF) was added at 0 °C under
J
J
J
J
J =
δ
16.07, 18.00, 18.50, 25.78, 28.78, 37.62, 50.57, 55.43, 55.77, TLC. The mixture was extracted with EtOAc and the combined
73.01, 75.07, 79.50, 111.37, 118.96, 120.68, 127.25, 127.66, organic layers were dried over anhydrous sodium sulfate and
128.06, 128.17, 128.45, 128.82, 135.51, 137.40, 138.76, concentrated in vacuum. The reaction mixture was then taken in
144.54, 150.61, 155.04, 171.83; HRMS (ESIꢀTOF) calculated MeOH and added to whic Pd/C was addded. It was then
for C37H50N2O4SiNa [M+Na]+: 669.3336; found: 669.3333.
degassed and subjected to hydrogenolysis at a pressure of 5 atm
for 3 h on a parr hydrogenator. After completion of the
reaction, the reaction mixture was filtered through celiteꢀ545
pad and it was purified by column chromatography on silica gel
(
S
)-3-((2
silyl)oxy)-3,5-dimethoxyphenyl)-3-hydroxypropanoyl)-4-
isopropyl-1-(( )-1-phenylethyl)imidazolidin-2-one (3m)
R,3R)-2-(benzyloxy)-3-(4-((tert-butyldimethyl
R
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 7

RSC Advances
Page 8 of 13
VJieowuArrtnicalelONnlainme e
ARTICLE
DOI: 10.1039/C6RA22026F
(60ꢀ120 mesh) using ethyl acetateꢀhexane (04:06) mixture as TOF) calculated for C18H20O4Na[M+Na]+: 323.1259; found:
eluent.
323.1278.
Yield = 75%; white solid, m.p. = 80 °C [Found [α]D20 = +9.8 (c
0.8 in CHCl3), lit. [α]D = +9.4 (c 0.8)]6; H NMR (400 MHz, Synthesis of (1
R,2
S
)-2-(benzyloxy)-1-phenylpropane-1,3-di
1
MeOD)
11.3 Hz, 1H), 3.65ꢀ3.69 (m, 1H), 3.78 (s, 3H), 4.48 (d,
Hz, 1H), 6.70 (d, = 8.1 Hz, 1H), 6.75 (dd, = 1.7, 8.1 Hz, hydroxyꢀ3ꢀphenylpropanoyl)ꢀ4ꢀisopropylꢀ1ꢀ((
1H), 6.93 (d, )imidazolidinꢀ2ꢀone 3a (0.2 g, 0.4 mmol, 1equiv.) in MeOH
= 1.6 Hz, 1H); 13C NMR (100 MHz, MeOD)
δ
3.51 (dd,
J
= 6.6, 11.3 Hz, 1H), 3.60 (dd,
J
= 3.7, ol (7)
J
= 6.2 To
a
stirred solution of
(
S
)ꢀ3ꢀ((2
R
,3
R
)ꢀ2ꢀ(benzyloxy)ꢀ3ꢀ
)ꢀ1ꢀphenylethyl
J
J
R
J
δ
47.12, 47.34, 47.55, 47.76, 47.98, 48.19, 48.40, 55.04, 62.64, 5mL was added NaBH4 (0.15 g, 4.1 mmol, 10 equiv.) and
74.64, 75.24, 110.32, 114.50, 119.50, 133.36, 145.38, 147.34; stirred for 3h. The progress of the reaction was monitored by
HRMS (ESIꢀTOF) calculated for C10H14O5Na[M+Na]+: TLC. The solvent was evaporated under vacuum. The crude
237.0739; found: 237.0734.
was purified by column chromatography using silica gel (60ꢀ
120 mesh) by eluting with petroleum ether/EtOAc (7:3) to
Synthesis of (2
propanoic acid (5)
R
,3
R
)-2-(benzyloxy)-3-hydroxy-3-phenyl afford the desired product.
Yield = 88%; colorless oil. [α]D = +48.0 (c 1, CHCl3); H
)ꢀ2ꢀ(benzyloxy)ꢀ3ꢀ NMR (400 MHz, CDCl3) 2.85 (brs, 2H), 3.59 (dd, = 4.6, 5.2
hydroxyꢀ3ꢀphenylpropanoyl)ꢀ4ꢀisopropylꢀ1ꢀ(( )ꢀ1ꢀphenylethyl) Hz, 1H), 3.75 (dq, = 4.7, 11.9 Hz, 2H), 4.44 (d, = 11.5 Hz,
imidazolidinꢀ2ꢀone 3a (0.2 g, 0.4 mmol, 1equiv.) in THF:H2O 1H), 4.52 (d, = 11.5 Hz, 1H), 4.92 (d, = 5.8 Hz, 1H), 7.21ꢀ
(3:1) was added in H2O2 (0.46 mL, 4.1 mmol, 10 equiv, 30 % 7.39 (m, 10H); 13C NMR (100 MHz, CDCl3)
61.45, 72.32,
20
1
To
a
stirring solution of
(
S
)ꢀ3ꢀ((2
R
,3
R
δ
J
R
J
J
J
J
δ
solution v/v in water) and LiOH.H2O (0.03 g, 0.8 mmol, 2 74.17, 82.33, 126.45, 127.77, 127.94, 128.01, 128.40, 128.49,
o
equiv.) at 0 C and stir for 1h at rt. The reaction was then 137.73, 141.04; HRMS (ESIꢀTOF) calculated for
quenched with 10% excess of 1.5 N Na2SO3 solution. Sodium C16H18O3Na[M+Na]+: 281.1154; found: 281.1098.
bicarbonate was added to the reaction mixture to get the pH at
9ꢀ10. THF was evaporated and the reaction mixture was Synthesis of (2
extracted with DCM to recover the chiral auxiliary. The phenylpropanamide (8)
aqueous layer was acidified to pH 1ꢀ2 using concentrated HCl To stirred solution of
and extracted with DCM, washed with water, brine dried over hydroxyꢀ3ꢀphenylpropanoyl)ꢀ4ꢀisopropylꢀ1ꢀ((
anhydrous sodium sulfate and concentrated to get the pure imidazolidinꢀ2ꢀone 3a (0.2 g, 0.4 mmol, 1equiv.) in THF (10
product. mL) was added benzylamine (0.06 mL, 0.6 mmol, 1.5 equiv.)
Yield = 85%; colorless oil. [α]D = +34.7 (c 1, CHCl3); H and stirred for 30 min. The progress of the reaction was
NMR (400 MHz, CDCl3) 4.14 (d, = 6.4 Hz, 1H), 4.36 (d, monitored by TLC. The reaction mixture was extracted with
= 11.6 Hz, 1H), 4.64 (d, = 11.6 Hz, 1H), 5.01 (d, = 6.4 Hz, EtOAc and the combined organic layers were dried over
1H), 5.41 (brs, 2H), 7.12ꢀ7.14 (m, 2H), 7.27ꢀ7.39 (m, 8H); 13C anhydrous sodium sulfate and concentrated in vacuum. The
NMR (100 MHz, CDCl3) 73.28, 74.24, 81.57, 126.95, 128.14, crude product was purified by flash column chromatography
R,3R)-N-benzyl-2-(benzyloxy)-3-hydroxy-3-
a
(
S
)ꢀ3ꢀ((2
R
,3
R
)ꢀ2ꢀ(benzyloxy)ꢀ3ꢀ
)ꢀ1ꢀphenylethyl)
R
20
1
δ
J
J
J
J
δ
128.28, 128.34, 128.47, 128.62, 136.46, 139.25, 174.17; HRMS using silica gel (60ꢀ120 mesh) by eluting with petroleum
(ESIꢀTOF) calculated for C16H16O4Na[M+Na]+: 295.0945; ether/EtOAc (6:4) to afford the desired product.
20
1
found: 295.0944.
Yield = 78%; Sticky. [α]D = +30.4 (c 1, CHCl3); H NMR
(400 MHz, CDCl3) 4.03 (d, = 7.3 Hz, 1H), 4.21 (q, = 11.3
)-ethyl 2-(benzyloxy)-3-hydroxy-3- Hz, 2H), 4.42 (d, = 6.0 Hz, 2H), 4.91 (d, = 7.3 Hz, 1H), 7.01
δ
J
J
Synthesis of (2
R,3
R
J
J
phenylpropanoate (6)
To stirring solution of
hydroxyꢀ3ꢀphenylpropanoyl)ꢀ4ꢀisopropylꢀ1ꢀ((
(bs, 1H), 7.05ꢀ7.08 (m, 2H), 7.12ꢀ7.14 (m, 2H), 7.26ꢀ7.29 (m,
)ꢀ2ꢀ(benzyloxy)ꢀ3ꢀ 3H), 7.30ꢀ7.34 (m, 3H), 7.35ꢀ7.39 (m, 3H), 7.47ꢀ7.50 (m, 2H);
)ꢀ1ꢀphenylethyl) 13C NMR (100 MHz, CDCl3) 42.94, 74.51, 75.28, 81.93,
a
(
S
)ꢀ3ꢀ((2
R
,3
R
R
imidazolidinꢀ2ꢀone 3a (0.2 g, 0.4 mmol, 1 equiv.) in EtOH 5mL 127.46, 127.57, 127.61, 128.22, 128.27, 128.31, 128.37,
was added K2CO3 (0.57 g, 4.1 mmol, 10 equiv.) and stirred for 128.63, 128.74, 136.44, 137.43, 139.88, 171.74; HRMS (ESIꢀ
4h. The progress of the reaction was monitored by TLC. The TOF) calculated for C22H23NO3Na[M+Na]+: 384.1576; found:
reaction mixture was filtered and solvent was evaporated under 384.1576.
vacuum. The crude reaction mixture was purified by column
chromatography using silica gel (60ꢀ120 mesh) eluting with 4-((tert-butyldimethylsilyl)oxy)-3,5-dimethoxybenzaldehyde
petroleum ether/EtOAc (09:01) to afford the desired product.
(9)
Yield = 90%; colorless oil. [α]D = +36.7 (c 1, CHCl3); H To a stirring solution of syringaldeyhde (2.0 g, 11.0 mmol,
NMR (400 MHz, CDCl3) 1.19 (t, = 7.1 Hz, 3H), 4.14 (d, 1equiv.) in DCM (30 mL) at 0 °C was added imidazole (1.87 g,
6.0 Hz, 1H), 4.16 (q, = 7.2 Hz, 2H), 4.40 (d, = 11.6 Hz, 1H), 27.4 mmol, 2.5 equiv.) and stirred for 30 min. TBSCl (1.82 g,
4.70 (d, = 11.6 Hz, 1H), 5.03 (d, = 6.1 Hz, 1H), 7.20ꢀ7.23 12.1 mmol, 1.1 eq) was then added to the reaction mixture at 0
(m, 2H), 7.30ꢀ7.41 (m, 8H); 13C NMR (100 MHz, CDCl3)
°C and stirred for another 1h at rt. The progress of the reaction
20
1
δ
J
J =
J
J
J
J
δ
14.06, 61.11, 72.96, 74.20, 81.85, 126.81, 128.00, 128.05, was monitored by TLC. The reaction mixture was extracted
128.08, 128.20, 128.41, 136.90, 139.61, 170.66; HRMS (ESIꢀ with DCM and the combined organic layers were dried over
8 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 2012

Page 9 of 13
Journal Name
RSC Advances
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ARTICLE
DOI: 10.1039/C6RA22026F
anhydrous sodium sulfate and concentrated in vacuum. The dry THF (100 mL) and under N2 environment was added
crude reaction mixture was purified by column chromatography sodium hydride (60% suspension in paraffin oil, 1.7 g, 41.3
using silica gel (60ꢀ120 mesh) by eluting with petroleum mmol, 1.2 equiv.) in portionꢀwise at 0 °C. After 1h,
ether/EtOAc (97:03) to afford the desired product.
bromoacetyl bromide (3.3 mL, 37.93 mmol, 1.1 equiv.) was
Off white solid, Yield = 92%, m.p. = 75ꢀ76 °C; [lit. m.p. = 78ꢀ added dropꢀwise and stirring was continued for another hour.
1
79 °C]6; H NMR (400 MHz, CDCl3)
9H), 3.88 (s, 6H), 7.11 (s, 2H), 9.83 (s, 1H); 13C NMR (100 with aq NaHCO3 and dried over anhydrous sodium sulfate. It
MHz, CDCl3) ꢀ4.55, 18.77, 25.66, 55.78, 106.71, 129.36, was evaporated under vacuum to give a gummy compound.
140.66, 151.97, 191.00.
Yield = 80%; Yellowish liquid. [α]D20 = +67.7 (c 1, CHCl3); 1H
NMR (400 MHz, CDCl3) 0.87 (d, = 6.9 Hz, 3H), 0.91 (d,
= 7.0 Hz, 3H), 1.62 (d, = 7.2 Hz, 3H), 2.40ꢀ2.48 (m, 1H), 2.99
To 4ꢀ((tertꢀbutyldimethylsilyl)oxy)ꢀ3,5ꢀdimethoxybenzaldehyꢀ (t, = 9.5 Hz, 1H), 3.14 (dd, = 2.9, 9.6 Hz, 1H), 4.23 (dt,
de (9) (4.08g, 13.49 mmol, 1.0 equiv.) was added DBU (2.11 3.3, 9.4 Hz, 1H), 4.53 (d, = 11.8 Hz, 1H), 4.74 (d, = 11.8
mL, 14.2 mmol, 1.05 equiv.) and triethyl phosphonoacetate Hz, 1H), 5.39 (q,
= 7.2 Hz, 1H), 7.32ꢀ7.42 (m, 5H); 13C NMR
(2.81mL, 14.16 mmol, 1.05 equiv.) and stirred for 4h. After (100 MHz, CDCl3) 14.44, 16.06, 17.98, 28.44, 29.08, 37.34,
δ 0.17 (s, 6H), 1.03 (s, The reaction mixture was quenched with aq NH4Cl, washed
δ
δ
J
J
(
E
)-ethyl 3-(4-hydroxy-3,5-dimethoxyphenyl)acrylate (10)
J
J
J
J =
J
J
J
δ
completion the reaction mixture was extracted with the ethyl 50.53, 55.51, 127.13, 128.06, 128.80, 138.76, 153.84, 166.34;
acetate. The organic layer was washed with 1N HCl solution HRMS (ESIꢀTOF) calculated for C16H21BrN2O2Na [M+Na]+:
and dried over sodium sulfate to give the crude product. The 375.0684; found: 375.0668.
crude product without purification was taken in acetonitrileꢀ
water mixture (40 mL, 38:02) and DBU (2.32 mL, 15.57 mL)
(E)-4-(3-hydroxyprop-1-en-1-yl)-2-methoxyphenol (13a)
was added and stirred for 3 h. The reaction mixture was To a stirred suspension of LiAlH4 (2.56 g, 67.36 mmol) in
extracted with ethyl acetate. Organic layer was washed with 1N freshly dried THF (200 mL), a solution of BnCl (7.7mL, 67.36
HCl, water and dried over anhydrous sodium sulfate. The mmol) in dry THF (20 mL) was added dropwise through
0
solvent was cocentrated in vacuum. The crude reaction mixture dropping funnel at 0 C. After the addition of BnCl the solution
was purified by column chromatography using silica gel (60ꢀ was allowed to warm to room temperature and stirred for 15ꢀ20
120 mesh) by eluting with petroleum ether/EtOAc (97:03) to min at room temperature. To this, a solution of (
afford the desired product. hydroxyꢀ3ꢀmethoxyphenyl) acrylate (10 g, 45 mmol) in (40
Light yellow solid, Yield = 90%, m.p.; experimental = 82 °C; m)L THF was added dropwise. The reaction mixture was
E)ꢀethyl 3ꢀ(4ꢀ
1
lit. = 83 °C; H NMR (400 MHz, CDCl3)
3H), 3.93 (s, 6H), 4.27 (q, = 7.1 Hz, 2H), 5.86 (brs, 1H), 6.32 cooled and slowly quenched with water, aq NaOH and again
(d, = 15.9 Hz, 1H), 6.78 (s, 2H), 7.61 (d, = 15.9 Hz, 1H); washed with water to form slurry which was filtered through
13C NMR (100 MHz, CDCl3)
14.35, 25.65, 56.32, 60.42, celite bed. The filtrate was taken in ethyl acetate, washed with
105.00, 116.00, 125.93, 137.07, 144.89, 147.21, 167.19.
δ 1.35 (t, J = 7.1 Hz, allowed to stir at room temperature for 2 h. Thereafter it was
J
J
J
δ
brine, and dried over anhydrous sodium sulfate. It was
evaporated under vacuum to afford the desired product.8
(
E
)-ethyl 3-(4-hydroxy-3-methoxyphenyl)acrylate (11)
Light yellow solid; Yield = 85%, m.p.; experimental = 74 °C,
1
To the stirred solution of ferulic acid (2.0 g, 8.92 mmol, 1.0 lit. = 75–80 °C; H NMR (400 MHz, CDCl3)
δ
3.92 (s, 3H),
= 6.0,
= 15.8 Hz, 1H), 6.87ꢀ6.94 (m, 3H); 13
was removed under vacuum and the compound was extracted NMR (100 MHz, CDCl3) 55.88, 63.87, 108.33, 114.49,
equiv.) in EtOH was added catalytic amount of H2SO4 and 4.32( dd,
J = 1.2, 6.0 Hz, 2H), 5.78 (s, 1H), 6.24(dt, J
refluxed for 4h. After completion of the reaction the solvent 15.8 Hz, 1H), 6.55 (d,
J
C
δ
with ethyl acetate. Organic layer was washed with aq. NaHCO3 120.31, 126.13, 129.24, 131.39, 145.58, 146.65.
solution, water and dried over anhydrous sodium sulfate. The
solvent was evaporated under vacuum to give the pure product
(2.11 g, 94%)
Light reddish solid; Yield = 94%, m.p.; experimental = 66 °C, lit. = 61 – 65 °C; H NMR (400 MHz, CDCl3)
(
E
)-4-(3-hydroxyprop-1-en-1-yl)-2,6-dimethoxyphenol (13b)
Light yellow solid, Yield = 84%, m.p.; experimental = 64 °C,
1
δ
3.91 (s, 6H),
= 5.9, 15.7
J
= 15.8 Hz, 1H), 6.65 (s, 2H); 13C NMR (100
1
lit. = 63ꢀ65 °C; H NMR (400 MHz, CDCl3)
Hz, 3H), 3.91 (s, 3H), 4.27 (q, = 7.1 Hz, 2H), 6.16 (s, 1H), Hz, 1H), 6.53 (d,
6.30 (d, = 15.9 Hz, 1H), 6.92 (d, = 8.2 Hz, 1H), 7.03 (d, MHz, CDCl3)
1.8 Hz, 1H), 7.07 (dd, = 1.8, 8.2 Hz, 1H), 7.62 (d, = 15.9 134.73, 147.11.
Hz, 1H); 13C NMR (100 MHz, CDCl3)
14.33, 55.90, 60.39,
109.47, 114.83, 115.53, 122.98, 126.97, 144.76, 146.89,
148.04, 167.40
δ 1.34 (t, J = 7.2 4.33 (d, J = 5.9 Hz, 2H), 5.63 (bs, 1H), 6.26 (dt, J
J
J
J
J
=
δ
56.27, 63.77, 103.29, 126.56, 128.21, 131.50,
J
J
δ
(
S
)-3-(2-(4-((
E)-3-((tert-butyldimethylsilyl)oxy)prop-1-en-1-
.
yl)-2-methoxyphenoxy)acetyl)-4-isopropyl-1-((
ethyl)imidazolidin-2-one 14a
To a stirred solution of ( )ꢀ4ꢀ(3ꢀhydroxypropꢀ1ꢀenꢀ1ꢀyl)ꢀ2ꢀ
methoxyphenol (2 g, 11.10 mmol) in 25 mL acetone at room
)ꢀ1ꢀ temperature was added K2CO3 (3.83 g, 27.74 mmol) and KI
phenylethyl]imidazolidinꢀ2ꢀone (8 g, 34.4 mmol, 1.0 equiv.) in (0.18 g, 1.109 mmol) and stirred for 15 minutes. A solution of
R)-1-phenyl
(
)
(
S
)-3-(2-bromoacetyl)-4-isopropyl-1-((
idazolidin-2-one (12
To stirred (S)ꢀ4ꢀisopropylꢀ1ꢀ[(R
R
)-1-phenylethyl)im
E
)
a
solution
of
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 9

RSC Advances
Page 10 of 13
VJieowuArrtnicalelONnlainme e
ARTICLE
)ꢀ3ꢀ(2ꢀbromoacetyl)ꢀ4ꢀisopropylꢀ1ꢀ((
DOI: 10.1039/C6RA22026F
(
S
R
)ꢀ1ꢀphenylethyl)imidaz hydroxypropanoyl)-4-isopropyl-1-((
R)-1-phenylethyl)imid
olidinꢀ2ꢀone (4.31 g, 12.20 mmol) in acetone (10 mL) was azolidin-2-one
(15a)
added to the reaction mixture. The reaction mixture was To a solution of (
S
)ꢀ3ꢀ(2ꢀ(4ꢀ((
E
)ꢀ3ꢀ((tertꢀbutyldimethylsilyl)
allowed to stir overnight at room temperature. After the oxy)propꢀ1ꢀenꢀ1ꢀyl)ꢀ2ꢀmethoxyphenoxy)acetyl)ꢀ4ꢀisopropylꢀ1ꢀ
completion of the reaction the solvent was evaporated and (( )ꢀ1ꢀphenylethyl)imidazolidinꢀ2ꢀone (1.0 g, 2.2 mmol, 1.0
R
water was added and the organic layer was separated, washed equiv.) in anhydrous THF (5 mL) under N2 environment was
with aq. NaHCO3 and brine. The solvent was evaporated under added LiHMDS solution (2.4 mL, 2.4 mmol, 1.1 equiv; 1 M in
vacuum to give the crude product as a sticky liquid. (4.77 g, THF) at –78 °C, and stirred for
1
h. 3,4ꢀ
95%).
Dimethoxybenzaldehyde (0.32 g, 2.4 mmol, 1.1 equiv.)
To a solution of (
S
)ꢀ3ꢀ(2ꢀ(4ꢀ((
E
)ꢀ3ꢀhydroxypropꢀ1ꢀenꢀ1ꢀyl)ꢀ2ꢀ dissolved in THF (3ml) was then added into the reaction
methoxyphenoxy)acetyl)ꢀ4ꢀisopropylꢀ1ꢀ((
R
)ꢀ1ꢀphenylethyl)imi
mixture and stirred for another hour. The reaction was
dazolidinꢀ2ꢀone (3 g, 6.63 mmol) in DCM (40 mL) was added quenched with saturated aq NH4Cl solution, extracted with
0
imidazole ( 1.13 g, 16.57 mmol) at 0 C and stirred for 30 min. EtOAc and further washed with brine. It was dried over
Then the solution of TBSCl (1 g, 6.63 mmol) in DCM (10 mL) anhydrous sodium sufate, concentrated and purified by column
was added to the reaction mixture. The reaction mixture was chromatography silica gel (60ꢀ120 mesh) by eluting with
allowed to warm to room temperature and stirred for another 2 petroleum ether:EtOAc (6:4) to afford the desired product.
20
1
h. After the completion of the reaction water was added to the Yield = 78%; Sticky. [α]D = +115.7 (c 1, CHCl3); H NMR
reaction mixture, the organic phase was separated and dried (400 MHz, CDCl3) 0.12 (s, 6H), 0.77 (d,
over anhydrous sodium sulfate. Solvent was evaporated under (d, = 7.0 Hz, 3H), 0.95 (s, 9H), 1.61 (d,
vacuum and the crude product was purified by column 2.40 (m, 1H), 2.99 (t,
chromatography to give the product as a sticky liquid. 1H), 3.67 (s, 3H), 3.88 (s, 3H), 3.92 (s, 3H), 4.26ꢀ4.29 (m, 1H),
Yield = 89%; Sticky. [α]D = +137.7 (c 1, CHCl3); H NMR 4.33 (dd, = 4.1, 5.2 Hz, 2H), 5.07 (brs, 1H), 5.38 (q, = 7.0
(400 MHz, CDCl3) 0.13 (s, 6H), 0.85 (d, = 6.9 Hz, 3H), Hz, 1H), 6.13 (dt, = 5.2, 15.8 Hz, 1H), 6.26 (d, = 7.5 Hz,
0.89 (d, = 7.0 Hz, 3H), 0.96 (s, 9H), 1.61 (d, = 7.2 Hz, 3H), 1H), 6.47 (d, = 15.8 Hz, 1H), 6.56 (d, = 8.2 Hz, 1H), 6.71
2.46 – 2.53 (m, 1H), 3.02 (t, = 9.6 Hz, 1H), 3.16 (dd, = 9.7, (dd, = 1.8, 8.2 Hz, 1H), 6.84 (d, = 1.8 Hz, 1H), 6.86 (d,
3.02 Hz, 1H), 3.75 – 3.79 (m, 1H), 3.93 (s, 3H), 4.23 (dt, 8.3 Hz, 1H), 7.13 (dd, = 1.8, 8.3 Hz, 1H), 7.17 (d, = 1.8 Hz,
9.5, 3.3 Hz, 1H), 4.35 (dd, = 5.2, 1.6 Hz, 1H), 5.36 (q,
= 7.2 1H), 7.31ꢀ7.41 (m, 6H); 13C NMR (100 MHz, CDCl3) ꢀ5.13,
Hz, 1H), 5.38 (d, = 2.3, 2H), 6.17 (dt, J = 15.7, 5.2 Hz, 1H), 14.51, 16.00, 17.98, 18.46, 24.69, 25.99, 37.74, 50.55, 55.61,
6.52 (d, = 15.8 Hz, 1H), 6.80 (d,
= 8.3, 1.8 Hz, 1H), 6.96 (d, = 1.8 Hz, 1H), 7.33ꢀ7.42 (m, 5H).
13C NMR (100 MHz, CDCl3)
J
= 6.8 Hz, 3H), 0.89
J
J = 7.2 Hz, 3H), 2.32ꢀ
J
= 9.5 Hz, 1H), 3.13 (dd, J = 2.3, 9.8 Hz,
20
1
J
J
δ
J
J
J
J
J
J
J
J
J
J
J
J =
J
=
J
J
J
J
J
J
J
= 8.3 Hz, 1H), 6.88 (dd,
J
55.81, 55.85, 55.91, 63.89, 74.84, 79.91, 110.33, 110.74,
110.90, 118.08, 119.18, 119.30, 127.09, 128.01, 128.08,
J
δ
ꢀ5.03, 14.39, 16.23, 18.02, 128.47, 128.81, 129.12, 132.32, 133.73, 138.80, 146.77,
18.56, 26.08, 28.37, 37.95, 50.52, 55.01, 56.00, 64.10, 68.52, 148.63, 150.42, 155.07, 170.35; ESIꢀHRMS (m/z): [M+Na]+
109.68, 113.68, 119.29, 127.25, 127.56, 128.14, 128.89, calculated for C42H58N2SiNaO9, 755.3704, found, 755.3703
129.47, 131.24, 138.85, 147.31, 149.53, 154.55, 168.48; ESIꢀ
HRMS (m/z): [M+Na]+ calculated for C32H46N2SiNaO5,
589.3074, found, 589.3075.
(S)-3-((2R,3R)-2-(4-((E)-3-((tert-butyldimethylsilyl)oxy)
prop-1-en-1-yl)-2-methoxyphenoxy)-3-(4-((tert-butyldi
phenylsilyl)oxy)-3-methoxyphenyl)-3-hydroxypropanoyl)-4-
(
S
)-3-(2-(4-((
yl)-2,6-dimethoxypheno-xy)acetyl)-4-isopropyl-1-((
nylethyl)imidazolidin-2-one 14b
E)-3-((tert-butyldimethylsilyl)oxy)prop-1-en-1-
R)-1-phe
isopropyl-1-((
Yield = 75%; Sticky. [α]D = +98.7 (c 1, CHCl3); H NMR
1H NMR (400 MHz, CDCl3)
0.14 (s,
= 6.8 Hz, 3H), 0.89 (d, = 7.0 Hz, 3H), 0.97 (s,
= 7.2 Hz, 3H), 9H), 1.13(s, 9H), 1.61 (d, = 7.1 Hz, 3H), 2.36ꢀ2.40 (m, 1H),
= 9.5 Hz, 1H), 3.12 (dd, = 2.8, 3.00 (t, = 9.5, 1H), 3.14 (dd, = 2.3, 9.8, 1H), 3.61 (s, 6H),
9.6 Hz, 1H), 3.84 (s, 6H), 4.25 (dt, = 3.2 Hz, 1H), 4.35 (dd, 3.92 (d, = 9.1 Hz, 1H), 4.26ꢀ4.30 (m, 1H), 4.35 (dd, = 1.6,
= 1.3, 5.0 Hz, 2H), 5.22ꢀ5.33 (m, 3H), 6.20 (dt, = 5.1, 15.7 5.2 Hz, 2H), 4.96 (t, = 8.1 Hz, 1H), 5.37 (q, = 7.1 Hz, 3H),
Hz, 1H), 6.51(d, 15.8 Hz, 1H), 6.59 (s, 2H), 7.28ꢀ7.38 (m, 5H); 6.11ꢀ6.18 (m, 2H), 6.47ꢀ6.50 (m, 2H), 6.68 (dd, = 1.9, 8.3 Hz,
13C NMR (100 MHz, CDCl3)
ꢀ5.12, 14.45, 16.10, 18.01, 1H), 6.70 (d, = 8.3 Hz, 1H), 6.83 (d, = 1.9 Hz, 1H), 6.88
18.48, 26.02, 28.49, 37.84, 50.27, 54.80, 56.19, 63.86, 71.92, (dd, = 2.0, 8.3 Hz, 1H), 7.05 (d, = 2.0 Hz, 1H), 7.3ꢀ7.43 (m,
R)-1-phenylethyl)imidazolidin-2-one (15b)
20
1
(
)
20
1
Yield = 85%; Sticky. [α]D = +89.7 (c 1, CHCl3); H NMR (400 MHz, CDCl3)
δ
δ
(400 MHz, CDCl3)
0.89 (d, = 7.0 Hz, 3H), 0.96 (s, 9H), 1.57 (d,
2.46ꢀ2.54 (m, 1H), 2.98 ( t,
δ
0.13 (6s, 6H), 0.84 (d,
J
J
= 6.8 Hz, 3H), 6H), 0.79 (d,
J
J
J
J
J
J
J
J
J
J
J
J
J
J
J
J
δ
J
J
J
J
103.69, 127.12, 127.95, 128.53, 128.73, 129.56, 132.82, 11H), 7.71ꢀ7.75 (m, 4H); 13C NMR (100 MHz, CDCl3) ꢀ5.08,
136.36, 138.94, 152.93, 154.50, 169.08; ESIꢀHRMS (m/z): 1.06, 14.58, 16.00, 18.01, 18.50, 19.83, 20.69, 26.03, 26.74,
[M+Na]+ calculated for C33H48N2SiNaO6, 619.3175, found, 28.98, 29.72, 37.78, 50.56, 55.43, 55.68, 55.77, 63.95, 75.09,
619.3180
80.18, 110.34, 112.02, 115.43, 118.35, 119.07, 119.35, 119.81,
120.08, 127.14, 127.50, 127.97, 128.11, 128.82, 129.22,
(
S
)-3-((2
R,3
R)-2-(4-((
E)-3-((tert-butyldimethylsilyl)oxy)prop 129.48, 129.57, 132.29, 133.72, 133.76, 134.48, 135.37,
-1-en-1-yl)-2-methoxyph-enoxy)-3-(3,4-dimethoxyphenyl)-3- 138.80, 144.74, 146.94, 150.15, 150.42, 155.14, 170.64; ESIꢀ
10 | J. Name., 2012, 00, 1-3
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ARTICLE
DOI: 10.1039/C6RA22026F
HRMS (m/z): [M+Na]+ calculated for C56H72N2Si2NaO8, (1
R S)-1-(4-hydroxy-3-methoxyphenyl)-2-(4-((E)-3-hydro
,2
xyprop-1-en-1-yl)-2,6-dimethoxyphenoxy)propane-1,3-diol
16c
Yield = 74%; colourless oil. [α]D = +6.7 (c 1, CHCl3). H
NMR (400 MHz, CDCl3) 3.51 (dd, J = 2.6, 12. Hz, 1H),
3.84(s, 9H), 3.90 (dd, = 7.3, 14.0 Hz, 1H), 4.12ꢀ4.15 (m, 1H),
4.30 (d, = 5.4 Hz, 2H), 5.00 (d, = 3.7 Hz, 1H), 6.29 (dt,
Yield = 74%; Sticky. [α]D = +77.8 (c 1, CHCl3); H NMR 5.5, 15.8 Hz, 1H), 6.53 (d, = 15.8 Hz, 1H), 6.63 (s, 2H),
(400 MHz, CDCl3) 0.15 (s, 6H), 0.61 (d, = 6.8 Hz, 3H), 6.74(d,
= 8.2 Hz, 1H), 6.82ꢀ6.84 (m, 1H), 6.94 (s, 1H); 13C
0.83 (d, = 7.0 Hz, 3H), 0.98(s, 9H), 1.11(s, 9H), 1.56(d, NMR (100 MHz, CDCl3) 55.93, 56.10, 60.52, 63.24, 72.49,
7.2 Hz, 3H), 2.11ꢀ2.16 (m, 1H), 2.96 (t, = 9.5 Hz, 1H), 87.03, 103.45, 108.56, 114.32, 118.77, 128.95, 130.37, 131.22,
3.11(dd, = 2.2, 9.6 Hz, 1H), 3.59 (s, 3H), 3.60 (s, 6H), 4.28 133.48, 134.44, 144.90, 146.71, 153.27; ESIꢀHRMS (m/z):
(dt, = 2.9, 9.5 Hz, 1H), 4.37(dd,
= 1.5, 5.1 Hz, 2H), 4.44 (d, [M+Na]+ calculated for C21H28NaO8, 429.1525, found,
= 8.8 Hz, 1H), 5.07 (t, = 6.7 Hz, 1H), 5.29 (q, = 7.1 Hz, 429.1520.
1H), 6.18 (d, = 5.5 Hz, 1H), 6.20 (dt, = 5.1, 15.8 Hz, 1H),
6.49ꢀ6.53(m, 3H), 6.66 (d, = 8.2 Hz, 1H), 6.81(dd, = 1.9, 8.2 (1
Hz, 1H), 7.06 (d, = 1.9 Hz, 1H), 7.27ꢀ7.30 (m, 2H), 7.32ꢀ7.42 methoxyphenoxy)propane-1,3-diol
(m, 9H), 7.7ꢀ7.75 (m, 4H); 13C NMR (100 MHz, CDCl3)
To a solution of (1 ,2 )ꢀ1ꢀ(3,4ꢀdimethoxyphenyl)ꢀ2ꢀ(4ꢀ((
5.12, 14.29, 16.02, 18.08, 18.51, 19.82, 26.03, 26.71, 28.89, hydroxypropꢀ1ꢀenꢀ1ꢀyl)ꢀ2ꢀmethoxyphenoxy)propaneꢀ1,3ꢀdiol
29.72, 37.29, 50.36, 55.08, 55.31, 55.81, 63.83, 74.37, 82.54, 16a) (0.1 g, 0.25 mmol) in ethyl (15 mL) acetate was added
979.4725, found, 979.4728.
(
)
20
1
(S)-3-((2R,3R)-2-(4-((E)-3-((tert-butyldimethylsilyl)oxy)pr
op-1-en-1-yl)-2,6-dimethoxyphenoxy)-3-(4-((tert-butyldip
henylsilyl)oxy)-3-methoxyphenyl)-3-hydroxy propanoyl)-4-
δ
J
isopropyl-1-((
R
)-1-phenylethyl)imidazolidin-2-one
(
15c
)
J
J
J =
20
1
J
δ
J
J
J
J
=
δ
J
J
J
J
J
J
J
J
J
J
J
R
,2
S
)-1-(3,4-dimethoxyphenyl)-2-(4-(3-hydroxypropyl)-2-
17
J
(
)
δ
ꢀ
R
S
E)ꢀ3ꢀ
(
103.39, 111.79, 119.43, 127.16, 127.46, 127.47, 127.97, catalytic amount of Pd/C. It was then degassed and subjected to
128.64, 128.70, 129.44, 129.48, 129.50, 132.63, 133.38, hydrogenolysis at a pressure of 5 atm for 1 h on a parr
133.78, 133.90, 135.35, 135.38, 136.85, 139.11, 144.49, hydrogenator. After completion of the reaction, the reaction
150.00, 152.20, 154.25, 169.51; ESIꢀHRMS (m/z): [M+Na]+ mixture was filtered through celiteꢀ545 pad and the filtrate thus
calculated for C57H74N2Si2NaO9, 1009.4831, found, 1009.4833. obtained was concentrated in vacuum to get the pure product.
18
Yield = 94%; colourless oil. [reported [α]D = 7.7 (c 1.9,
20
1
(1
R
,2
S
)-1-(3,4-dimethoxyphenyl)-2-(4-((
E
)-3-hydroxyprop-
16a
Yield = 80%; yellowish oil. [α]D = +7.8 (c 1, CHCl3); H 2H), 3.64 (m, 1H), 3.74 (s, 3H), 3.77 (s, 3H), 3.77 (s, 3H), 3.82
MeOH), observed [α]D = 9.2 (c 1.9, MeOH).9; H NMR (400
1-en-1-yl)-2-methoxy phenoxy) propane-1,3-diol
(
)
MHz, CDCl3) 1.76 (m, 2H), 2.55 (t, J = 7.2 Hz, 2H), 3.55 (m,
20
1
NMR (400 MHz, CDCl3)
3.87 (s, 3H), 3.88 (s, 3H), 3.90 (s, 3H), 3.92 (dd,
Hz, 1H), 4.17(, m, 1H), 4.32 (dd, = 1.5, 5.7 Hz, 2H), 4.99 (d, = 8.0 Hz, 1H), 6.84 (d,
= 4.8 Hz,1H), 6.28 (dt, = 5.7, 15.8 Hz, 1H), 6.56(d, = 15.8 (100 MHz, CDCl3) δ 31.5, 33.9, 55.6, 55.6, 55.6, 60.6, 61.6,
Hz, 1H), 6.84 (d, = 8.3 Hz, 1H), 6.88ꢀ6.92 (m, 3H), 6.97 (m, 72.5, 86.3, 109.4, 110.8, 112.2, 118.4, 119.6, 120.9, 132.9,
2H); 13C NMR (100 MHz, CDCl3)
δ
3.68 (dd,
J
= 3.4, 12.2 Hz, 1H), (m, 1H), 4.07 (m, 1H), 4.90 (d,
J
= 3.5 Hz, 1H), 6.60 ( d,
J
=
J
= 5.8, 12.2 8.0 Hz, 1H), 6.66 (brs, 1H), 6.72 (d,
J
= 8.0 Hz, 1H), 6.75 (d,
J
J
J
= 8.0, 1H), 6.92 (brs, 1H); 13C NMR
J
J
J
J
δ
55.94, 60.80, 63.62, 72.76, 137.4, 144.7, 148.1, 148.6, 150.6; HRMS (ESIꢀTOF) calculated
87.30, 109.22, 109.85, 111.05, 118.41, 120.08, 120.71, 128.12, for C21H28O7Na [M+Na]+: 415.1733; found: 415.1729
130.52, 132.40, 133.04, 146.58, 148.53, 149.06, 151.52; ESIꢀ
HRMS (m/z): [M+Na]+ calculated for C21H26NaO7, 413.1576, References
found, 413.1582.
(1
R
,2
S
)-1-(4-hydroxy-3-methoxyphenyl)-2-(4-((
E)-3-hydrox
1. R. Mahrwald, in Modern Methods in Stereoselective Aldol Reactions,
yprop-1-en-1-yl)-2-methoxyphenoxy)propane-1,3-diol
Yield = 82%; colourless oil. [α]D = +10.8 (c 1, CHCl3); H 2. (a) K. S. Kim, S. D. Hong, Tetrahedron. Lett. 2000, 41, 5909; (b)
(
16b
)
WileyꢀVCH Verlag GmbH & Co. KGaA, 2013.
20
1
NMR (400 MHz, DMSOꢀd6)
(s, 3H), 4.08 (m, 2H), 4.30 (m, 1H), 4.61 (t,
4.7 (t, = 4.86 Hz, 1H), 4.80 (t, = 5.5 Hz, 1H), 5.32 (d,
4.6 Hz, 1H), 6.22 (15.9, 5.3 Hz, 1H), 6.43 (bd, = 15.9 Hz,
δ
3.59 (m, 2H), 3.72 (s, 3H), 3.73
M. B. Andrus, B. V. S. Sekhar, T. M. Turner, E. L. Meredith,
J
= 5.6 Hz, 1H),
Tetrahedron. Lett. 2001, 42, 7197; (c) M. T. Crimmins, J. She, J.
J
J
J
=
Am. Chem. Soc
Morris, J. Am. Chem. Soc
Hulme, J. Org. Chem. 2008
J. L. Leighton, A. S. Kim, J. Org. Chem
Andrus, B. V. S. Sekhar, E. L. Meredith, N. K. Dalley, Org. Lett
.
2004
,
126, 12790; (d) D. A. Evans, S. L. Bender, J.
1988 110, 2506; (e) S. Fanjul, A. N.
73, 9788; (f) D. A. Evans, J. R. Gage,
1992 57, 1961; (g) M. B.
J
.
,
1H), 6.67 (d,
J
= 8.0 Hz, 1H), 6.77 (dd,
J
J
= 8.1, 1.7 Hz, 1H),
= 8.4 Hz, 1H), 6.99
,
6.84 (dd, = 8.3, 1.8 Hz, 1H), 6.92 (d,
J
.
,
(m, 1H), 6.99 (m, 2H), 8.76 (s, 1H); 13C NMR (100 MHz,
DMSOꢀd6) 55.31, 55.49, 60.00, 61.52, 71.51, 83.59, 109.75,
111.30, 114.45, 115.41, 118.93, 119.34, 128.37, 128.45,
129.91, 133.09, 145.32, 146.85, 147.45, 149.60; ESIꢀHRMS
(m/z): [M+Na]+ calculated for C20H24NaO9, 399.1420, found,
399.1428.
.
,
2000
2003
,
,
2, 3035; (h) M. T. Crimmins, P. J. McDougall, Org. Lett
5,
591; (i) W. R. Roush, L. A. Pfeifer, T. G. Marron, J. Org.
63, 2064; (j) J. Bajget, M. Caba, E. Galvez, P. Romea,
F. Urpi, M. F. Bardia, J. Org. Chem. 2012 77, 8809; (k) M. T.
Crimmins, A. L. Choy, J. Am. Chem. Soc 1999
Carda, J. Murga, E. Falomir, F. González,
Chem. 1998
,
,
.
,
121, 5653; (l) M.
J. A. Marco,
Tetrahedron
,
2000
,
56, 677; (m) I. Paterson, D. J. Wallace, S. M.
This journal is © The Royal Society of Chemistry 2012
J. Name., 2012, 00, 1-3 | 11

RSC Advances
Page 12 of 13
ARTICLE
VJieowuArrtnicalelONnlainme e
DOI: 10.1039/C6RA22026F
Velázquez, Tetrahedron Lett. 1994, 35, 9083; (n) J. Murga, E.
Falomir, F. González, M. Carda, J. A. Marco, Tetrahedron
58, 9697.
, 2002,
3. Chiral catalysts and ligands for aldol reaction; (a) S. G. Nelson,
Tetrahedron: Asymmetry. 1998 , 357; (b) M. B. Andrus, J. Liu, Z.
Ye, J. F. Cannon, Org. Lett., 2005 , 3861; (c) E. M. Carreira, A.
Fettes, C. Marti, Org. React 2006 67, 1; (d) C. Guillena, C. Najera,
D. J. Ramon, Tetrahedron: Asymmetry 2007 18, 2249; (e) B. M.
Trost, C. S. Brindle, Chem. Soc. Rev 2010 39, 1600; (f) M.
Markert, M. Mulzer, B. Schetter, R. Mahrwald, J. Am. Chem. Soc
,
9
,
7
.
,
.
,
.
,
.
.
2007
2008
,
,
129, 7258. (g) S. E. Denmark. W. J. Chung, J. Org. Chem
73, 4582. (h) B. M. Trost, W. M. Seganish, C. K. Chung, D.
2012 18, 2948.
4. G. Khatik. V. Kumar, V. A. Nair, Org. Lett., 2012
5. Lignan isolation: (a) F. Cutillo, B. D’Abrosca, M. Dellagreca, A.
Fiorentino, A. Zarelli, J. Agric. Food Chem. 2003 51, 6165; (b) E.
J. Jeong, J. H. Cho, S. H. Sung, S. Y. Kim, Y. C. Kim, Bioorg. Med.
Chem. Lett. 2011 21 2283; (c) X. X. Huang, C. C. Zhou, L. Z. Li,
F. F. Li, L. L. Lou, D. M. Li, T. Ikejima, Y. Peng, S. J. Song,
Bioorg. Med. Chem. Lett 2013, 23, 5599; (d) S. Li, K. Landquist, A.
F. A. Wallis, Phytochem. 1998 49, 2125; (e) F. Li, X. W. Yang,
Phytochem 2008 69, 765; (f) W. Xu, H. Wang, G. X. Zhou, X. S.
Yao, J. Asian Nat. Prod. Res. 2010 12, 874; (g) J. Lee, E. K. Seo,
D. S. Jang, T. J. Ha, J. P. Kim, Chem. Pharm. Bull 2009 57, 298;
(h) Y. B. Liua, J. J. Qina, X. R. Chenga, J. X. Zhua, F. Zanga, H. Z.
Jin, W. D. Zhang, Helv. Chim. Acta 2011 94 (i) R. Q. Mei, Y. H.
Wang, G. H. Du, G. M. Liu, L. Zhang, Y. X. Cheng, J. Nat. Prod
2009 72, 621; (j) H. H. Xiao, Y. Dai, M. S. Wong, X. S. Yao,
Fitoterapia 2014 94, 29. Lignan Synthesis: (a) K. Li, R. F. Helm,
J. Chem. Soc., Perkin Trans. I 1996, 2425; (b) S. Hishiyama, Y.
Otsuka, M. Nakamura, S. Ohara, S. Kajita, E. Masai, Y. Katayama,
Tetrahedron Lett. 2012 53, 842; (c) C. E. Rye, D. Barker, Eur. J.
Med. Chem. 2013 60, 240; (d) J. Buendia, J. Mottweiler, C. Bolm
Chem. Eur. J. 2011 17, 13877; (e) C. Curti, F. Zanardi, L.
Battistini, A. Sartori, G. Rassu, L. Pinna, G. Casiraghi, J. Org.
Amans, Chem. Eur. J
.
,
,
14, 2442.
,
,
,
.
,
.
,
,
.
,
,
,
;
.
,
,
,
,
,
,
Chem
.
2006
,
71, 8552; (f) P. R. Reddy, B. Das, RSC Adv.
,
2014
,
4,
7432; (g) S. K. Das, S. K. Das, G. Panda, G. Eur. J. Org. Chem
.
2010, 5100; (h) M. Nagaraju, R. Chandra, B. Bhimrao, B. B.
Gawali, Synlett 2012
,
23, 1485; (i) M. Chouhan, R. Sharma, V. A.
14, 5672.
Nair, Org. Lett., 2012
,
6. M. DellaGreca, A. Fiorentin, P. Monaco, L. Previtera, Synth.
Commun. 1998 28, 3693.
7. G. P. Pettit, N. Melody, A. Thornhill, J. C. Knight, T. L. Gory, C. L.
Herald, J. Nat. Prod. 2009 72, 1637.
8. X. Wang, X. Li, J. Xue, Y. Zhao, Y. Zhang, Y. Tetrahedron Lett.
2009 50, 413.
9. W. Xu, H. Wang, G. X. Zhou, X. S. Yao, J. Asian Nat. Prod. Res.
2010 12, 874.
,
,
,
,
12 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C6RA22026F
Graphical Abstract
Anti selective glycolate aldol reactions of (S)-4-isopropyl-1-[(R)-1-phenyl
ethyl]imidazolidin-2-one: application towards the asymmetric synthesis of 8-4'-
oxyneolignans
Mukesh Gangar, Avinash Ittuveetil, Sandeep Goyal, Anang Pal, Harikrishnan M., Vipin A. Nair*
aDepartment of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research,
Sector 67, Mohali, Punjab 160062, India.
This journal is © The Royal Society of Chemistry 2013
J. Name., 2013, 00, 1-3 | 1